1. Field of the Invention
The invention relates, as novel and useful industrial products, to novel 1-oxaspiro[2,5]octan-6-ol derivatives. The invention also relates to a process for preparing them and to their use in pharmaceutical compositions for use in human or veterinary medicine, or in cosmetic compositions.
2. Description of Related Art
It is known that angiogenesis is the formation of new blood capillaries from already-existing blood vessels. Angiogenesis plays an important role in the development of embryonic tissue, but hardly ever features in healthy adult tissue.
The development of new blood vessels may be observed under non-physiological conditions. This development may play a beneficial role, such as, for example, in the case of cicatrization. However, its action is usually deleterious: the development of tumours, accompaniment to chronic inflammatory diseases.
The role of angiogenesis is most frequently manifested in the case of tumours: it has been demonstrated that, during the growth phase, tumours have absolute need of the development of new blood vessels.
Although the link between the development of a tumour and angiogenesis was proposed by Folkman more than 30 years ago (Folkman, J., New. Engl. J. Med. 1971, 285, 1182), it has only been in the last ten years that the possibility of antitumoural therapies based on controlling angiogenesis has been widely accepted. Currently, many anti-angiogenic molecules are in the course of clinical study (Norrby, K., APMIS, 1997, 105, 417-437; Arbiser, J. L., J. Am. Acad. Dermatol. 1996, 34(3), 486-497; Fan, T-P. D., TIPS, 1995, 16, 57-66). As has recently been shown (Boehm, T., Folkman, J. et al. Nature, 1997, 390, 404-407), an antitumoural therapy based on controlling angiogenesis is less likely to give rise to resistance phenomena.
Angiogenesis is also associated with the pathological process of various inflammatory diseases. In this respect, angiogenesis inhibition may have an implication in the treatment and prevention of these diseases. Abnormal angiogenesis is thus involved in various diseases of inflammatory nature, for instance rheumatoid arthritis, or others, for instance atherosclerosis and retinopathy of diabetic origin.
Many research groups have attempted to discover novel molecules capable of inhibiting angiogenesis, such as, for example, Taylor by application of Protamine (Taylor, S. et al., Nature, 1982, 297, 307), or the use of heparin in the presence of cortisone, by Folkman (Folkman, J. et al., Science, 1983, 221, 719).
In dermatology, it is very widely accepted that a deregulation of angiogenesis control is associated with a multitude of disorders: tumours, psoriasis, haemangiomas (exaggerated angiogenesis) (Creamer, D. et al., Br. J. Dermatol, 1997, 136 (6), 859-865; Jackson, J. R. et al. FASEB.J, 1997, 11(6), 457-465), ulcers (deficient angiogenesis).
To date, steroids have been used for the treatment of haemangiomas, the efficacy of which is probably due to their anti-angiogenic activity.
It is also clear that increased attention is being given to angiogenesis as a target for a therapeutic intervention in other dermatological complaints. This is manifested, for example, clinically by the design of studies focused on angiogenesis (Gradishar, W. J. Invest New Drugs, 1997, 15(1), 49-59) and by the increasing number of reports, articles and publications relating to angiogenesis (Ann. Rep. Med. Chem. 1997, 32, 161-170; Ann. Rep. Med. Chem. 1992, 27, 139-148).
Finally, it should be noted that various classes of dermatologically active molecules (retinoids, vitamin 1,25-di-OH-D-3) are now being examined for their potential role on angiogenesis (Eur J. Pharmacol. 1993, 249 (1), 113-116; Cancer Lett. 1995, 89 (1) 117-124).
In the field of angiogenesis, fumagillin and its derivatives are of particular importance: TNP-470 (AGM 1470) described in patent EP 357 061 and its successor, FR-118 847 described in patent EP 386 667, are active in many angiogenesis models and have recognized antitumoural activity (Logothetis, C. J., Clin Cancer Res 2001 May; 7(5):1198-1203).
These compounds are described as having activity in angiogenesis inhibition, the suppression of cell proliferation, and immunosuppression.
These compounds are synthesized by standard semi-synthetic processes as described in patents EP 357 061 and EP 386 667 cited above.
Other fumagillin derivatives, such as the 6-epifumagillols described in patent EP 387 650, also have applications in angiogenesis inhibition, the suppression of cell proliferation and immunosuppression. In this case also, they are synthesized via a semi-synthetic process.
The mode of action of these compounds remained unexplained until 1997 when a biological target, a methionine aminopeptidase: MetAP-2, was identified (Griffith, E. C. et al., Chem Biol, 1997, 4(6), 461-471). The inhibitory activity of various fumagillin derivatives with respect to this enzyme shows good correlation with the anti-angiogenic effect.
The discovery of this enzyme has enabled better targeting of the desired activity and the synthesis of novel fumagillin analogues with better biological activity, while at the same time reducing their side effects. In particular, the mode of action proposed by Griffith, Liu and Clardy (a; Liu, S. et al. Science, 1998, 282, 1324-1327. b; Griffith, E. C. et al. Proc. Natl. Acad. Sci. USA, 1998, 95, 15183-15188) for fumagillin and its analogues involves a crucial interaction between the exocyclic epoxide of these molecules and a cobalt atom located at the active site of MetAP-2 followed by opening of this epoxide by a histidine of the active ring, this sequence leading to an irreversible inhibition of MetAP-2. This model suggests that substituents introduced into the positions of the fumagillin ring system that are still free (positions 7 and 8 of the 1-oxaspiro[2,5]octane ring system) would be capable of interfering with the enzyme close to the active ring, thus disrupting the activity of the inhibitors. The Applicant has used this enzyme in order to identify novel fumagillin derivatives and to exploit better anti-angiogenic candidates for the topical and systemic treatment of complaints that may involve a proliferative, inflammatory and/or immunosuppressant component, especially in the field of dermatology.
The Applicant has thus invented novel derivatives by developing a novel process of total synthesis. This total synthesis gives access to analogues that are very difficult or even impossible to prepare by semi-synthesis. In particular, it allows the functionalization of positions 7 and 8 of the 1-oxaspiro[2,5]octane ring system and the introduction of a wide variety of side chains, and also allows the synthesis of optically active products. This process of total synthesis also offers the advantage of allowing better control and a production that is more economical than the previous semi-synthetic processes.
The Applicant has moreover discovered that a key area in the formation of the active molecule-biological target complex concerns the substituents in positions 7 and 8 of the 1-oxaspiro[2,5]octane ring system, and that it could be advantageous to be able to benefit from novel fumagillin derivatives bearing substitution in positions 7 and 8 of the 1-oxaspiro[2,5]octane ring system and/or a modified side chain and not comprising an epoxide function, so as to be able to identify better anti-angiogenic candidates for the topical and systemic treatment of complaints that may involve a proliferative, inflammatory and/or immunosuppressant component, especially in the field of dermatology.
Such derivatives may also be obtained according to the present invention.